Abstract Background: In pts with HR-positive metastatic breast cancer, endocrine resistance is a major clinical problem. Ganetespib is a small molecule inhibitor of heat shock protein 90 (HSP90), a molecular chaperone protein that regulates post-translational folding of numerous client proteins including estrogen and progesterone receptor. In preclinical HR-positive breast cancer models, ganetespib impairs endocrine resistance and reduces heterogeneity in the disease control achievable by hormonal therapies. Trial Design and Eligibility: This is a randomized phase II study designed to evaluate the efficacy of ganetespib in combination with fulvestrant compared to fulvestrant alone. Pts with endocrine-resistant, HR-positive metastatic breast cancer and up to 1 prior line of metastatic chemotherapy are eligible. Endocrine resistance is defined as relapse while on or within 1 year of completion of adjuvant endocrine therapy (ET) or progression through at least one line of ET for advanced disease. Patients are treated with fulvestrant 500 mg IM on Cycle 1 Day 1 (C1D1) and C1D15, C2D1, and D1 of each subsequent 28-day cycle. Ganetespib is administered at a starting dose of 200 mg/m2 IV on Days 1, 8, and 15 of each cycle. Pts undergo optional research biopsies at baseline and time of progression. Pts with accessible disease undergo a required research biopsy on C2D9. Circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMCs) are collected at baseline, C2D8, C2D9, and time of progression. Pts who progress on fulvestrant may cross over to the combination. Aims: The primary endpoint is progression-free survival. Secondary endpoints include safety and tolerability, objective response rate by RECIST 1.1, clinical benefit rate, and overall survival. Correlative aims include comparison of biomarkers on the C2D9 biopsy in pts treated with fulvestrant alone versus the combination of fulvestrant plus ganetespib, analysis of CTCs and pharmacodynamic markers in PMBCs. Statistical Methods: Pts will be randomized 1:2 to receive fulvestrant alone or the combination of fulvestrant plus ganetespib. The total accrual goal is 71 pts. The expected accrual rate is 3.5-4.5 pts per month over a period of ∼20 months; it is anticipated at ∼15% of pts may be censored for PFS, with similar probability on both arms. There will be 80% power to detect a prolongation of true median PFS from 4.0 months to 8.0 months, using a one-sided 0.05 log-rank test. Acrrual: To date, 15 of 71 planned pts have been enrolled. Funding: The trial is supported by a grant from the Susan G. Komen foundation and funding from Synta Pharmaceuticals. Contact information: nlin@partners.org. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-05.